title: TET1 plays an essential oncogenic role in MLL-rearranged leukemia.
abstract: The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Wang
authors.forename: Gia-Ming
authors.initials: GM
authors.lastname: Hong
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Keith
authors.initials: K
authors.lastname: Szulwach
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Craig
authors.initials: C
authors.lastname: Street
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Meelad
authors.initials: M
authors.lastname: Dawlaty
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D046228:Microarray Analysis; D006899:Mixed Function Oxygenases; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C097899:homeobox protein HOXA9; C011865:5-hydroxymethylcytosine; C090466:proto-oncogene protein Pbx3; D051788:Myeloid-Lymphoid Leukemia Protein; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D011495:Histone-Lysine N-Methyltransferase